This application is responsive to the NCI Provocative Question #9 (RFA-CA-15-008). Cognitive dysfunction (chemobrain) is an important adverse sequel of cancer chemotherapy, the study of which has been identified by the NCI as a poorly understood problem for which current management or treatment strategies are limited or ineffective. Our preliminary data show that neuronal ryanodine receptor/calcium release channels (RyR2) on the endoplasmic reticulum (ER) become oxidized and leaky in mice treated with doxorubicin or methotrexate plus 5-FU. These mice exhibit cognitive dysfunction that can be improved using a novel orally available small molecule drug (Rycal, S107) developed by the co-PI that fixes leaky RyR2 channels. The goals of this application are to: (1) establish and characterize a murine model of advanced human breast cancer that can be used to study whether intracellular calcium (Ca2+) leak via oxidized neuronal RyR2 on the ER is a novel mechanism underlying cancer chemotherapy-induced neurocognitive dysfunction; and (2) test whether the novel drug Rycal (S107) that fixes leaky neuronal RyR2 channels in vivo can prevent chemobrain. The proposed studies will have important clinical relevance as the Rycal S107 is in the same chemical class as two closely related Rycals that are currently in clinical testing for heart and muscle disorders, and to date both have excellent safety profiles. S107 has the advantage that it is concentrated >10-fold in the brain. (Although S107 is patented by Columbia University, US 8,710,045, 04/29/14, the drug is available to all investigators and the applicant receives no proceeds from its sale). This application is bolstered by preliminary data showing that commonly used chemotherapeutics cause cognitive dysfunction in C57BL6 mice that can be prevented using the Rycal S107, and by our published data showing that leaky neuronal RyR2 channels can cause stress-induced cognitive dysfunction (post-traumatic stress disorder, PTSD) that can be ameliorated by oral treatment with S107. This application aims to make the novel mechanistic link between chemobrain and PTSD - intracellular Ca2+ leak - and to test a potential novel therapy that prevents this leak and prevents chemobrain.